Obesity is a major risk factor for type 2 diabetes mellitus.1, 2 The proopiomelanocortin (POMC)-derived peptide, α-melanocyte-stimulating hormone (α-MSH) is involved in the regulation of food intake and energy homeostasis in mammals3 and the reduction of inflammatory reactions.4-6 Evidence indicates that the expression of α-MSH mRNA is increased in the pituitary of genetically obese mice (ob/ob)7 and that α-MSH suppresses feeding behavior in mice and fish.8, 9 On the basis of evolutionary conservation theory, studies suggest that α-MSH has a species-dependent regulatory function in energy homeostasis and has two tissue-dependant and opposing roles. In the central nervous system (CNS), α-MSH increases sensitivity to insulin,10 while in the periphery, α-MSH seems to play a pivotal role in insulin resistance.10α-MSH is a potent agonist of melanocortin 1 receptors (MC1R) and melanocortin 4 receptors (MC4R).11 MC4R knockout mice have been shown to develop a maturity onset obesity syndrome characterized by hyperphagia, hyperglycemia and hyperinsulinemia.12 It is shown that MC4R mutations are linked to severe obesity in French children with variable expression and penetrance.13 Additionally, MTII (a specific synthetic MC3R/MC4R agonist) inhibits food intake in rats.14 Notably, studies indicate that analogs of α-MSH influence blood glucose in mouse models of obesity.10 
Recent studies have shown that the serine protease prolylcarboxypeptidase (PRCP) inactivates α-MSH by catalyzing the cleavage of the carboxyl terminus Pro-Val, suggesting that PRCP may have orexigenic action.15 PRCP activates three distinct and seemingly unrelated (Ang II, Ang 1-8) to angiotensin 1-7 (Ang 1-7), and angiotensin III (Ang III, Ang 2-8) to angiotensin 2-7 (Ang 2-7); ii. PRCP potentiates vasodilation via activation of the plasma kallikrein-kinin system (KKS), resulting in the release of bradykinin (BK) from high molecular weight kininogen (HK).16 BK is an important vascular mediator, causing vasodilation and is a leading inducer of edema;17, 18 iii. PRCP mediates cell growth and inflammation via inactivation of α-MSH.
Current medications for obesity are limited in effectiveness, suggesting the existence of a novel, uncharacterized mechanism that contributes to this condition. Since mutations in the MC4R gene can cause monogenic obesity,19 applicants proposed that selective inhibitors of PRCP might be a promising therapeutic option for some people with elevated PRCP-induced α-MSH1-12 production, especially those for whom other anti-obesity therapy has failed. The advantages of this approach are three-fold. First, PRCP inhibitors decrease inflammation through reducing the synthesis of BK and Ang 1-7. Secondly, PRCP inhibitors may promote the activation of anti-inflammatory mediators via MC1R-dependent and MC1R-independent pathways, acting through an α-MSH/NF-κB and/or α-MSH/IL10-mediated mechanisms.6, 20, 21 Thirdly, PRCP inhibitors reduce food-intake in patients via MC4R, acting through an α-MSH-mediated mechanism. PRCP inhibitors may represent a new class of dual-acting anorexigenic and anti-inflammatory agents, which may reduce the risk of heart disease in obese patients. Recently, researchers have disclosed the identification of a potent and selective small molecule PRCP inhibitor to validate PRCP as a valid target for the development of anti-obesity drugs.22 